Random ethylene oxide copolymer and non-random alkylene oxide(s) polymer

ABSTRACT

A polymeric material comprised of (i) at least one random copolymer comprised of ethylene oxide and one or more other alkylene oxide(s) and (ii) at least one non-random polymer comprised of one or more poly(alkylene oxide)s has been discovered. Preferably, it is a polymer alloy. Alkylene oxide homopolymers or block copolymers may be the non-random polymer. In a related discovery, an adhesive material can be made by suspending (a) particles in (b) a matrix of at least one poly(ethylene oxide) copolymer of ethylene oxide and propylene oxide, or a combination thereof. The handling characteristics may be adjusted for different utilities (e.g., from runny oil to hard wax). Applications include use as adhesive, cohesive, filler, lubricant, surfactant, or any combination thereof. In particular, the hard materials may be used for cleaning or waxing.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 10/545,105,filed Aug. 10, 2005, now U.S. Pat. No. 7,553,913; which claims prioritybenefit of provisional Application No. 60/446,534, filed Feb. 12, 2003;which are incorporated herein by reference. This is also related toApplication No. PCT/US2004/004174, filed on Feb. 12, 2004; which is alsoincorporated by reference.

FIELD OF THE INVENTION

The invention relates to a composition comprised of (i) at least onerandom copolymer comprised of ethylene oxide and other alkylene oxide(s)and (ii) at least one non-random polymer comprised of one or morepoly-(alkylene oxide)s (e.g., homopolymers and/or block copolymers).

BACKGROUND OF THE INVENTION

In the medical and surgical fields, there has been an unmet need forcompositions with handling characteristics that range from a viscous oilto a hard wax. Desirable compositions would have one or more of thefollowing properties: biocompatibility, non-metabolizable underphysiological conditions, low toxicity and corrosiveness, readilyeliminated from the body in unmodified form, easy and inexpensive tomanufacture and store, long lived, and variable viscosity and hardness.Preferably, such compositions would be resorbed and readily eliminatedby the body after they had served their intended purpose.

Such compositions would have a wide range of uses. For uses in thesurgical field, compositions which have handling characteristicsresembling a hard, adherent wax could be useful as a hemostatic agentthat could be used to prevent bleeding from the surfaces of bones.Compositions with oily, greasy, or waxy characteristics (in ascendingdegrees of hardness) can be used as lubricants of surgical instrumentsand implants. Applications would include use as a carrier or excipientfor particulate implantable materials, bioactive agents, and otherpharmaceutical agents. The compositions are also suitable as a matrixfor particulate material, adhesive/cohesive, filler, and/or lubricant;they may also be used as dispersing or suspending agents, emulsifiers,extenders, thickeners, and/or bodying agents for compositions, inparticular for cosmetic and pharmaceutical formulations.

Until our discovery, there were no biocompatible, substantiallynon-toxic, water-soluble compositions available with handlingcharacteristics that range from a grease to a wax over a temperaturerange from about 25° C. to about 37° C. for medical and surgicalapplications, which can be formulated to be substantially free of water(e.g., less than about 5% or about 1% water). All previously knownwater-soluble compositions with such handling characteristics andintended for medical or surgical applications contained water in theirformulation.

Currently, the medical and surgical need for the appropriateformulations is being met in a number of different and less thanacceptable ways. Most have the problem of either not being completelybiocompatible or not having handling characteristics that are wellsuited for their intended application. Beeswax, commonly used as a bonehemostatic agent, is non-resorbable, interferes with bone healing, andcauses inflammatory reactions. Compounds derived from biologicalsources, such as collagen, have the potential to cause immune reactionsand may even have the potential to spread infectious agents. Manycompounds in use fall into the category of hydrogels. Hydrogels consistof a three dimensional network of hydrophilic polymer chains in anaqueous medium that are cross-linked through either chemical or physicalbonding. Theoretically, at least, the network is infinite and thepolymer chains are effectively a single molecule. By definitionhydrogels contain at least 10% water by total weight (or volume); butmore commonly contain 10 to 50 times more water than polymer (w/w/ orw/v). Hydrogels in general do not have ideal physical characteristicsfor a material that needs to be handled and manipulated into position.They are typically elastic but not plastic, lacking malleability andductility, and are often labile when exposed to compressive, tensile orshearing forces, leading to irreversible fracturing or tearing of thematerial. The water within hydrogels also may affect the lifetime ofbioactive agents. Hydrocarbon compounds, either petroleum based (e.g.,paraffin, petrolatum) or from other sources such as beeswax orplant-derived waxes, have the appropriate handling characteristics, butare not water soluble. Silicon oils and silicon gels are neitherbiologically inert nor water soluble. Thus, suitable polymers fortherapeutic use remain to be discovered.

In the fields of surgery and dentistry, there is a need for animplantable material that contains a particulate component that canserve as a framework for tissue ingrowth. The particulate component canbe selected from a broad range of natural and synthetic implantablesubstances, including but not limited to native autogenous bone orcartilage, bone or cartilage from other sources that is either grafteddirectly or after processing, collagen, hydroxyapatite,polymethylmethacrylate (PMMA), polytetrofluoroethylene (PTFE),polyethylene, and dimethylpolysiloxane.

The performance of particulate implants is markedly improved by theaddition of a matrix to temporarily adhere the particles to one anotherand to form a putty that serves to improve the handling characteristicsand acts as a delivery system. The majority of matrices in use ordisclosed in the prior art are aqueous solutions or hydrogels includingcollagen, glycerol, polysaccharides, mucopolysaccharides, hyaluronicacid, plasdones, and polyvinylpyrrolidones (PVP).

Collagen, in the form of gelatin, has been used in ARTEPLAST® from RofilMedical International. It is an injectable material comprised ofmicrospheres of PMMA suspended in a gelatin solution. Followingimplantation, the gelatin is resorbed and replaced by native collagen.Another formulation, ARTECOLL® is a product currently available inEurope and Canada. It is comprised of smooth PMMA spheres, suspended inbovine collagen from a closed pharmaceutical herd at a concentration of25% PMMA/75% collagen, by weight with 0.3% lidocaine. Because ARTECOLL®contains bovine collagen, testing for allergy to such collagen isrecommended. Bovine collagen carries the risk of an immunogenic reactionby the recipient patient. Recently, it has been found that a disease ofcattle, bovine spongiform encephalopathy (BSE) is transmitted frombovine tissue to humans. Thus, bovine collagen carries a risk of diseasetransmission and is not a desirable matrix for allograft bone. Humancollagen is free of these animal-based diseases. However, collagenabsorbs slowly in the human body, particularly in a bony site with a lowdegree of vascularity.

Glycerol is used as a matrix for demineralized allograft bone in theform of a gel. For example, GRAFTON from Osteotech is a simple mixtureof glycerol and lyophilized, demineralized bone powder (U.S. Pat. No.5,073,373). GRAFTON works well to allow the surgeon to place theallograft bone at the site. But glycerol has a very low molecular weight(92 daltons) and is very soluble in water, the primary component of theblood which flows at the surgical site. Glycerol also experiences amarked reduction in viscosity when its temperature rises from roomtemperature (typically 22° C. in an operating room) to the patient'sbody temperature (typically 37° C.). This combination of high watersolubility and reduced viscosity causes the allograft bone with aglycerol matrix to be runny and to flow away from the site almostimmediately after placement. This prevents the proper retention of theallograft bone within the site as carefully placed by the surgeon. Theuse of the low molecular weight glycerol carrier also requires a highconcentration of glycerol to be used to achieve the bulk viscosity.Glycerol and other low molecular weight organic solvents are also toxicand irritating to the surrounding tissues. U.S. Pat. No. 6,306,418describes the use of glycerol as the matrix for TEFLON particles in thefield of urology.

Surgical implantation of artificial sphincters has often been employedto treat patients suffering from urinary incontinence. The most commonand widely used method to treat patients with urinary incontinence isperiurethral injection of a composition commercially sold as POLYTEF,which is a paste comprising a 1:1 by weight mixture of glycerin matrixand TEFLON particles. After injection, however, the glycerin is readilydissipated into the body over a period of time and then metabolized oreliminated, leaving only the TEFLON particles. A drawback of such apaste is that the size of the particles is sufficiently small so as toallow them to migrate to other locations of the body such as the lungs,brain, etc. TEFLON particles have been known to induce tissue reactionand form TEFLON-induced granulomas in certain individuals. This tissuereaction to TEFLON also has caused concerns for the patient's health.

U.S. Pat. No. 4,191,747 discloses a bone defect treatment with denaturedbone meal freed from fat and ground into powder. The bone meal is mixedwith a polysaccharide in a solution of saline and applied to the bonedefect site.

U.S. Pat. No. 5,290,558 discloses a flowable, demineralized bone powdercomposition using an osteogenic bone powder mixed with a low molecularweight polyhydroxy compound possessing from 2 carbons to about 18carbons including a number of classes of different sugars such asmonosaccharides, disaccharides, water-dispersible oligosaccharides, andpolysaccharides.

U.S. Pat. No. 5,356,629 discloses making a rigid gel in the form of abone cement to fill defects in bone by mixing biocompatible particlespreferably PMMA coated with polyhydroxyethylmethacrylate in a matrix(e.g., hyaluronic acid) to obtain a molded semi-solid mass which can besuitably worked for implantation into bone. The hyaluronic acid can alsobe utilized in monomeric form or in polymeric form preferably having amolecular weight not greater than about one million daltons. It is notedthat non-bioabsorbable but biocompatible particles can be derived fromxenograft bone, homologous bone, autogenous bone, as well as othersubstances. The bioactive substance can also be an osteogenic agent suchas demineralized bone powder, in addition to morselized cancellous bone,aspirated bone marrow, and other autogenous bone sources. This is acement used for implantation of hip prosthesis.

Ersek et al. describe the clinical use of soft particles delivered as abiphasic hydrogel material (Plast. Reconstr. Surg. 95:985-992, 1995).The material comprises solid particles of dimethylpolysiloxane rangingin size from 100 micron to 600 micron suspended in a hydrogel of theplasdone family.

BIOPLASTIQUE® material from Uroplasty, a biphasic material, consists ofsolid silicone particles, ranging from 100 microns to 400 microns insize, suspended in PVP. But this material elicits a low-gradeinflammatory response upon injection. In a rabbit model, the hydrogelmatrix is reabsorbed by the body within 96 hours and eliminated in anintact form by the kidneys. The hydrogel matrix is replaced by fibrinand inflammatory cells. Fibroblasts are recruited into the area by 14days and begin to replace the fibrin bed with a collagen matrix. Thecollagen encapsulates and localizes the silicone, and animal studieshave not shown any evidence of foreign body migration. Deposition ofcollagen progresses, replacing the organic component of the material ina ratio slightly greater than 1:1. Connective tissue cells develop andreplace about 30% of the matrix with host collagen fibrils. At 382 days,fibrosis was complete and each individual particle appeared to beencased in its own fibrous capsule. This material has the distinctdisadvantage of using silicone, which may be of concern when evaluatinglong-term safety.

U.S. Pat. No. 5,641,502 discloses a material comprising (i) a polymerderived from hydroxyacids, tactones, carbonates, etheresters,anhydrides, orthoesters, and copolymers, terpolymers and/or blendsthereof and blended with (ii) at least one surface active agent which isfrom 2% to 55% by weight block copolymer of polyoxyethylene andpolyoxypropylene. Additional, a leaching agent from 0% to 70% by weightmay be included in the blend to provide a porous microstructure.

Poloxamer-based thermoreversible hydrogels are being developed for useas a drug delivery system. The cooled poloxamer solution containing thedrug is liquid at less than 10° C. It is easily administered to thedesired location in the body and the drug-containing solution forms ahydrogel as it warms to 37° C. The solidified gel remains at the site,slowly releasing the drug by diffusion and/or gradual solubilization ofthe gel matrix. Such compositions are distinguished from our inventionbecause they do not include a random copolymer component, and do nothave the wide variety of utilities disclosed herein.

U.S. Pat. No. 6,281,195 discloses a poloxamer hydrogel matrix for thedelivery of osteogenic proteins. In particular, poloxamer 407 (PLURONIC®F127) is used in the form of a hydrogel. But hydrogels havedisadvantages if used as the matrix instead of the present composition.

Therefore, in the field of surgery, a biocompatible, substantiallynon-toxic composition with adhesive and cohesive properties is needed.Hemostasis is an example of an application of such a composition. Boneis a structure with a rich blood supply. Blood within bone typicallycirculates through a system of canals and within the bone marrow and, assuch, hemostasis using traditional methods, such as an electrocautery,is ineffective. Traditionally, bone hemostasis is obtained by applying aformulation primarily composed of beeswax onto the cut surface of thebleeding bone. The beeswax adheres to the bone and serves to act as atamponade of the canals and bone marrow space, eventually leading to theclotting of the blood. Unfortunately, beeswax is not cleared by the bodyand acts to interfere with bone healing and inflammatory reactions areknown.

Provisional U.S. Appln. No. 60/162,347 discloses a water-soluble wax foruse as a bone hemostasis agent whose handling characteristics aim tosimulate those of beeswax. The application of alkylene oxide blockcopolymers over the bleeding sites of the bone for hemostasis wasdescribed. Advantages over prior art methods include the finding thatbone growth was not inhibited, and the water-soluble composition wasresorbed and excreted. The preferred material described is a 9:1 blendby weight of two block copolymers: poloxamer 235 (PLURONIC® P85) andpoloxamer 238 (PLURONIC® F88). But a random copolymer component wasneither taught nor suggested. Blending poloxamer 235 and poloxamer 238requires a precise combination of ingredients and snap cooling topreserve the blend, which is not a readily static mixture, and obtainthe desired mechanical properties.

The formulations of bone hemostasis agents in the prior art lack one ormore of the following attributes: biocompatibility, superior handlingcharacteristics, and easy manufacture and storage. In contrast,preferred embodiments of the invention provide a biocompatible,substantially non-toxic, stable (i.e., non-metabolizable and readilyeliminated) composition with superior handling characteristics.

It is an objective of the invention to provide a composition withsuperior properties for medical and surgical applications.Biocompatibility, substantial non-toxicity, water solubility, desirablehandling properties (e.g., hardness, ductility, malleability),emulsification, filling, slipperiness (e.g., lubrication), surfaceactivity (e.g., surface activity), tackiness (e.g., adhesion, cohesion),and thickening are characteristics of particular interest. Furtheradvantages of the invention are described.

SUMMARY OF THE INVENTION

The invention relates to compositions which may be used in medicine,surgery, dentistry, and various other commercial (i.e., non-medical)utilities. Processes for making and using this product and relatedproducts are provided.

A polymeric composition may be comprised of (i) at least one randomcopolymer comprised of ethylene oxide and one or more other alkyleneoxide(s) and (ii) at least one non-random polymer comprised of one ormore poly(alkylene oxide)s. The non-random polymer may be a homopolymeror a block copolymer of at least two poly(alkylene oxide)s. Thecomposition may be a polymer alloy. The composition can bebiocompatible, substantially non-toxic to living tissue, substantiallynon-metabolizable under physiological conditions, readily eliminated inunmodified form by the body, or any combination thereof. The compositioncan be formulated to be water soluble, but contain no water (i.e.,substantially anhydrous except for minor amounts of absorbed water). Thecomposition may have a consistency of a viscous oil to a hard wax(including a grease or paste). Water may be added prior to use orabsorbed in the body, but it is preferred to formulate the compositionas a flowable liquid with less than about 5% or 1% water before use inthe body or further formulation. Generally, it is not considered ahydrogel, especially before use in the body or further formulation.

Choice of the other alkylene oxide(s), molecular mass, mass ratio, andprocedures during manufacture can affect the compound's properties:e.g., hardness, adhesiveness, cohesiveness, ductility, malleability, andhardness. For example, “working” the composition may change itscharacteristics by homogenizing its internal structure. Handlingcharacteristics may be similar when compared between ambient temperature(e.g., 20° C. to 25° C.) and body temperature (e.g., 37° C. or 40° C.).

Such products may be administered to the body (e.g., applied topicallyto the skin or other exposed tissue, depot or suppository, implanted orplaced therein, ingested, injected). Biocompatibility and substantialnon-toxicity are desirable properties for such applications.

Another composition may be made by suspending (a) particles in (b) acarrier comprised of (i) at least one random copolymer comprised ofethylene oxide and one or more other alkylene oxide(s) and (ii) at leastone non-random polymer comprised of one or more poly(alkylene oxide)s.This material may be adhered to hard tissue (e.g., tooth, bone,cartilage) with minimal adverse reaction by the tissue, the matrix maybe resorbed to leave behind a porous framework of solid particles, andtissue may grow within the pores. In a preferred embodiment, thecomposition is made by mixing at an about 1:3 mass ratio of poloxamer188 with 22K random alkylene oxide copolymer (AOC) to form a soft wax.

A polymeric alloy composition may be made by blending (a) at least onerandom copolymer comprised of ethylene oxide and one or more otheralkylene oxide(s) and (b) at least one non-random polymer comprised ofone or more poly(alkylene oxide)s.

An objective of the invention is to provide carriers and excipients.They may take advantage of any one of the beneficial propertiesdescribed herein to deliver a therapeutic (e.g., bioactive agent,device, instrument) in the body of a human or animal. For example, theexcipient may act as a lubricant to assist the passage or placement ofthe therapeutic in the body or a part thereof.

A further objective is to provide for an oral composition to be used asan excipient or as a laxative. In like fashion, it is intended toprovide a component for cosmetic and pharmaceutical formulations fortopical application, particularly for uses in which drawing fluid awayfrom the application site is desirable.

Another objective is to provide a waxy material for utilities such aslost wax casting and water-soluble crayons. The composition may be usedas a cleanser or stain remover. Lubricants, either flowable liquid orsolid, to ease passage and to decrease friction are provided.

Further aspects of the invention will be apparent to a person skilled inthe art from the following detailed description and claims, andgeneralizations thereto. In particular, a reference to a “composition”in the context of this invention includes compositions containing onlypolymers (e.g., blend or alloy of random copolymer and non-randompolymer) as well as compositions with non-polymeric additives (e.g.,bioactive agents, medical/surgical devices, implants, instruments, solidor porous particles, therapeutic or non-therapeutic products, andcombinations thereof).

BRIEF DESCRIPTIONS OF THE DRAWINGS

FIG. 1 illustrates crystals of compositions made with random AOC (about22,000 g/mol; 50:50 mass ratio of ethylene oxide to propylene oxide) andblock AOC, poloxamer 188 (PLURONIC® F68), in the following proportionsof non-random polymer to random copolymer (F68:22K random AOC): (A)2:98, (B) 5:95, (C) 10:90, (D) 20:80, (E) 30:70, (F) 40:50, (G) 50:50,(H) 60:40, (I) 70:30, (J) 80:20, (K) 90:10, or (L) 98:2. Single crystalswere formed in all of the compositions, without gaps appearing betweenthe crystals (i.e., a single component solid). This shows that they wereall comprised of a compatible, homogeneous blend. Spherulite sizes didnot appear to vary between mass ratios of 5:95 and 50:50. Above a massratio of 60:40, crystal size increased and spherulite rings andfractures became apparent. Fractures gave an opaque appearance to thesolid sticks. They were clearly seen as black lines within and betweenthe crystals for mass ratios between and 70:30 and 98:2.

FIG. 2 illustrates crystals of compositions with the following randomAOC and non-random polymer in equal mass proportions: (A) 3.5K PEOhomopolymer and 12K random AOC, (B) poloxamer 188 and 12K random AOC,(C) 35K PEO homopolymer and 12K random AOC, (D) 2K PEO homopolymer and3.9K random AOC, and (E) 7.5K PEO homopolymer and 3.9K random AOC, FIGS.2A-2B are examples of compatible, miscible blends under the conditionsand at the resolution used here. Spherulites without gaps between thecrystals show that only a single phase was observed. FIGS. 2C-2E areexamples of incompatible (immiscible) blends. There are clearly multiplephases observed, PEO in the melt phase forms discreet sphericalcrystalline droplets as it cools. FIG. 2D illustrates the presence ofsome compatible (fibrous) regions. Under the definition of AOC alloyused herein, FIGS. 2A-2B illustrate examples of polymer alloys butincompatible compositions are illustrated in FIGS. 2C-2E.

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

Those skilled in the art will appreciate that the compositions describedhere may be utilized for a wide variety of applications. The presentinvention provides for water soluble, biocompatible, substantiallynon-toxic, substantially non-metabolizable, and/or readily eliminatedcompositions. Compositions which are polymer alloys are preferred. A“polymer alloy” defined under the conditions described here is amacroscopically homogeneous composition of two or more different speciesof polymers which is comprised of compatible polymer blends and misciblepolymer blends, but this definition excludes incompatible polymerblends. The specified attributes and handling characteristics of thecomposition can be designed as shown herein by appropriate selection ofpolymers, as well as their molecular masses and ratios.

The composition may be made by blending a polymeric material comprising(i) at least one random alkylene oxide copolymer (random AOC) and (ii)at least one non-random alkylene oxide polymer. The random AOC may becomprised of ethylene oxide and one or more alkylene oxide(s). Thenon-random polymer may be homopolymer (AOH) and/or copolymer (blockAOC).

Poly(alkylene oxide)s (PAO) which are also known as polyoxyalkylenes(POA) are made by the polymerization of alkylene oxides (e.g., ethyleneoxide, propylene oxide, butylene oxide). A homopolymer is formed onlyfrom one type of alkylene oxide while a copolymer is formed from two ormore different alkylene oxides, known as alkylene oxide copolymers(AOC). Examples of the former are poly(ethylene oxide) (PEO), which is apolymer of ethylene oxide (EO), and poly(propylene oxide) (PPO), whichis a polymer of propylene oxide (PO). Poly(ethylene oxide) is alsocommonly known as polyethylene glycol (PEG) or polyoxyethylene (POE).The molecular weight of such polymers is generally characterized as theaverage of a distribution of lengths (or repeat units). PEO isamphiphilic, extremely hydrophilic, water soluble, biocompatible, andsubstantially non-toxic and is produced commercially in a wide range ofmolecular weights (200 g/mol to 10 million g/mol). Low molecular weightforms of POE below 600 g/mol (i.e., oligomeric forms with less than 14EO monomer units on average) are low-viscosity liquids at roomtemperature; PEO is a solid at 25° C. above 600 g/mol. PPO differs fromPEO in that it is hydrophobic, generally insoluble in water except atlow molecular weights (less than about 1 kg/mol), and is liquid at 25°C. even at high molecular weights (e.g., 6 kg/mol). The homopolymer mayhave a molecular mass of at least about 1 kg/mol, about 2 kg/mol, orabout 5 kg/mol; the molecular mass may also be not more than about 10kg/mol, about 20 kg/mol, or about 50 kg/mol. The compound may be furtherdescribed by intermediate ranges using the aforementioned upper andlower limits.

In addition to the standard linear forms, branched or star forms ofpoly-(alkylene oxide)s are produced by initiating the polymerizationreaction with a polyfunctional initiator with multiple hydroxyl-,amino-, or thiol-groups each of which can serve as a starting point forpolymer chain growth. For example, the use of glycerol (three hydroxylgroups) as an initiator results in a three-armed branched polymer, whilepentaerythritol results in a four-armed polymer. PEO molecules of thistype are available commercially (e.g., the Sunbright™ series, NOFCorporation, Japan) with anywhere from three to more than one hundredarms. Conventionally, polymers of this type with 3 to 10 arms are termed“branched” while those with more than 10 arms are termed “star”polymers. “Comb” copolymers are similar to branched and star forms, butthe initiator for comb copolymers is a polyfunctional polymer withmultiple hydroxyl-, amino-, or thiol-groups spaced along the initiatorbackbone, each of which can serve as a staring point for polymer chaingrowth. “Graft” copolymers are made by the addition of pendant polymerchains along a polymer backbone that possesses unsaturated C═C bonds orpendant functional groups (e.g., hydroxyl) from which pendant chains canbe added by using a reactive monofunctional polymer chain.

All poly(alkylene oxide)s contain, in addition to multiple alkyleneoxide-derived repeat units, a single residue corresponding to themolecule used to initiate the polymer synthesis. For linear polymers,this may be an alkylene glycol corresponding to the alkylene oxide usedfor the synthesis (e.g., ethylene glycol and ethylene oxide,respectively) and thus the initiator-derived residue will beindistinguishable from the other repeat units in the polymer chain. Butsmall molecules other than alkylene glycols are often used asinitiators, examples include methanol or N-butanol (for linear polymers)and trimethylol propane, glycerol, and pentaerythritol (for branchedpolymers) or ethylene diamine. The mass of initiator relative to themass of the final polymer chain is generally very small and can usuallybe neglected. Thus, the term poly(alkylene oxide) is used here in itscustomary sense, and includes both poly(alkylene oxide)s initiated withan alkylene glycol molecule and poly(alkylene oxide)s initiated withanother small molecule.

Water-soluble poly(alkylene oxide)s are substantially non-toxic whenapplied to the skin or taken orally, and PEG and some poloxamers (e.g.,F68 or poloxamer 188) have been evaluated for medical and surgicalapplications, and demonstrated to be suitable for parenteral use.

Random Alkylene Oxide Copolymer

Random AOC preferably has a molecular mass from about 1 kg/mol to about1000 kg/mol (i.e., average molecular mass of a distribution ofpolymers). It may have a molecular mass of at least about 5 kg/mol,about 10 kg/mol, or about 20 kg/mol; the molecular mass may also be notmore than about 25 kg/mol, about 50 kg/mol, or about 200 kg/mol. Themass ratio of ethylene oxide to the other alkylene oxide(s) preferablyis from about 5:95 to about 95:5. It may have a mass ratio of at leastabout 10:90, about 25:75, or about 40:60; the mass ratio may also be notmore than about 60:40, about 75:25, or about 90:10. The compound may befurther described by intermediate ranges using the aforementioned upperand lower limits.

A preferred random AOC is a copolymer of ethylene oxide andC_(n)H_(2n)O, where n=3 to 6. In a particular embodiment, the molecularmass may be from about 15 kg/mol to about 30 kg/mol. Preferably, themolecular mass is at least about 20 kg/mol and/or not more than about 25kg/mol and has a mass ratio of ethylene oxide to propylene oxide that issubstantially equimolar.

In contrast to block AOC, a random copolymer of alkylene oxide(s) can besynthesized directly from an appropriate mixture of alkylene oxides, andthus the different alkylene oxide molecules are added to the polymerchain in a random sequence. The random AOC may be copolymer(s) of EO andPO. Random EO/PO copolymers have a certain combination of propertieswhich distinguish them from EO and PO homopolymers and block AOC, andwhich make them uniquely useful as excipients for certain pharmaceuticalapplications. The most important of these is that they combine two ofthe desirable properties of PEO and PPO—i.e., they are liquids at roomtemperature and above over a wide range of molecular weights, but arewater soluble. In contrast, except at very low molecular weights (lessthan 1000 g/mol), PPO is not water soluble and POE is a solid. Also,unlike most block copolymers, random AOC do not in the pure stateself-associate to form structured domains or a crystalline structure(hence their liquid nature). Like all other PAO, they are soluble inselected organic solvents, able to solubilize many organic and inorganicsubstances including hydrophobic drugs that are poorly soluble in water,and have very low toxicity.

There is some evidence that small PEO molecules (600 g/mol or less) maybe metabolized in vivo to produce oxalate, which is toxic. But largerPAO are known to be effectively inert and non-metabolizable in vivo, andare excreted unchanged. This provides a further advantage of the highermolecular weight random PAO liquids vs. liquid PEO.

A preferred embodiment uses a random alkylene oxide copolymer with amolecular weight of about 22 kg/mol (22K random AOC) and an EO:PO massratio of about 50:50. Such a compound is commercially available fromBASF Corporation as PLURACOL® V-10 According to its manufacturer, V-10was developed specifically for use in water-glycol fire-resistanthydraulic fluids and is additionally suitable as a water-soluble,cutting and grinding fluid and in various metal working applications.Furthermore, the manufacturer discloses that complete toxicityinformation on V-10 has not yet been fully developed and that the normalprecautions exercised when handling any chemical should be used whenworking with V-10: e.g., eye protection should be used and prolongedcontact with the skin should be avoided. Another preferred embodiment isa random alkylene oxide copolymer with a molecular weight of about 12kg/mol (12K random AOC) and a mass ratio EO:PO of about 75:25.

Random AOC are produced by several manufacturers including BASF, DowChemical, and Sigma/Aldrich under the trade names PLURADOT®, PLURACOL®,SYNALOX® EPB, and EMKAROX® among others. They are available in a rangeof EO:PO ratios and molecular weights (e.g., 1000 to 22,000 g/mol) andin linear and branched geometries, and are commonly characterized bytheir viscosity rather than molecular weight. Dow Chemical provides anumber of random AOC with molecular weights in the range of 1,500 to4,900 including those with the following codes: EP 530, EP 1730, EP 435,EP 1660, 15-200, 112-2, UCON 50-HB-5100, and UCON 50-HB-660.Sigma/Aldrich provides a number of random AOC with molecular weights inthe range of 2,500 to 12,000 including those with the following codes:43,819-7, 43,820-0, 43,818-9, 40,918-9. Medical applications for PAOhave been focused on block AOC. In contrast, the use of random AOC hasalmost exclusively been restricted to nonmedical applications, and theirpotential for providing medical benefits has been largely overlooked.

Block Alkylene Oxide Copolymer

Block AOC may be linear or branched, and preferably has a molecular massfrom about 1 kg/mol to about 100 kg/mol (i.e., average molecular mass ofa distribution of polymers). It may have a molecular mass of at leastabout 2 kg/mol, about 4 kg/mol, about 6 kg/mol, or about 10 kg/mol; themolecular mass may also be not more than about 10 kg/mol, about 15kg/mol, about 20 kg/mol, or about 50 kg/mol. A preferred block AOC is acopolymer of ethylene oxide and C_(n)H_(2n)O, where n=3 to 6 (propyleneoxide is preferred). The mass ratio of ethylene oxide to the otheralkylene oxide(s) preferably is from about 5:95 to about 95:5. It mayhave a mass ratio of at least about 10:90, about 25:75, or about 40:60;the mass ratio may also be not more than about 60:40, about 75:25, orabout 90:10. The compound may be further described by intermediateranges using the aforementioned upper and lower limits. Preferredembodiments use a block alkylene oxide copolymer with (1) a molecularmass from about 6 kg/mol to 10 kg/mol and an EO:PO mass ratio from 60:40to 90:10 or (2) a molecular mass from about 6 kg/mol to 10 kg/mol and anEO:PO mass ratio from 60:40 to 90:10.

Block copolymers are synthesized sequentially. First, a central block iscommonly polymerized from one type of alkylene oxide (e.g., PO), thenone or more outer blocks are added to the ends in a secondpolymerization step using another alkylene oxide (e.g., EO). Poloxamers(e.g., PLURONIC® copolymers from BASF) are linear A-B-A triblockcopolymers of EO and PO having the general formula(EO)_(x)(PO)_(y)(EO)_(x), where x, y are the average number of EO and POmonomer units in the block. A hydrophobe of the desired molecular weightis made by the controlled addition of propylene oxide to thetwo-hydroxyl groups of propylene glycol; ethylene oxide is then added tosandwich the hydrophobic block between hydrophilic blocks. Thehydrophilic blocks constitute from 10% to 80% by weight of the finalmolecule. Poloxamers are available in a range of molecular weights from1,100 to 15,000 g/mol and PO:EO ratios of 9:1 to 2:8. Meroxapols (e.g.,PLURONIC® R from BASF) are linear triblock copolymers similar topoloxamers but with a reversed (B-A-B) structure and hence the generalformula (PO)_(y)(EO)_(x)(PO)_(y). A hydrophile of the desired molecularweight is made by the controlled addition of ethylene oxide to ethyleneglycol; propylene oxide is then added to create hydrophobic blocks onthe outsides of the central hydrophilic block. The physical propertiesof block copolymers range from low-viscosity liquids to pastes to solid,depending upon the precise combination of molecular weight and EO:POratio (higher molecular weight and higher EO proportion increasing themelting point). See review by Schmolka (J. Am. Oil Chem. Soc.,54:110-116, 1977).

In BASF's PLURONIC® code, the alphabetical designation is derived fromthe physical form of the product at room temperature: L for liquids, Pfor pastes, and F for flake (solid) forms. In the numerical designation,the first digit (or the first two digits in a three numeral code)multiplied by 300 indicates the approximate molecular weight of thehydrophobe. The last digit multiplied by 10 indicates the approximatepercentage (w/w) of the hydrophile in the PLURONIC® copolymer. Preferredblock AOC are poloxamer 108 (PLURONIC® F38), poloxamer 188 (PLURONIC®F68), poloxamer 238 (PLURONIC® F88), poloxamer 288 (PLURONIC® F98),poloxamer 338 (PLURONIC® F108), poloxamer 237 (PLURONIC® F87), poloxamer335 (PLURONIC® P105), and poloxamer 407 (PLURONIC® F127).

Poloxamer 188 (PLURONIC® F68) (8350 g/mol, 80% POE), has been used fortopical wound cleaning and has been approved for intravenous use as anemulsifier for perfluorocarbon oxygen-carrying formulations. Aqueoussolutions of a poloxamer such as poloxamer 407 (PLURONIC® F127) (12,500g/mol, 70% POE) at a sufficiently high concentration (typically greaterthan about 30% w/v) are used as hydrogel formulations for drug delivery.These are preferred block AOC.

Poloxamines (e.g., TETRONIC® block copolymers from BASF), are 4-armedsymmetrical poly(alkylene oxide) block polymers prepared using anethylene diamine initiator with the general formula[(EO)_(x)-(PO)_(y)]₂-NCH₂CH₂N-[(PO)_(y)-(EO)_(x)]₂, and are anotherexample of an alkylene oxide copolymer that may be used to make thecomposition. Reverse poloxamines, in which the four PEO blocks are addedbefore the four PPO blocks, can also be used.

Blending Random and Non-Random Alkylene Oxide Polymers

A discovery that forms one basis for the present invention is thatcertain random AOC are capable of forming either compatible or miscibleblends (i.e., alloys) with selected solid AOH and block AOC. Thispreviously unrecognized property differentiates random AOC from otherliquid polymers, such as low molecular weight PEO and PPO, which do notform alloys with solid PEO or poloxamers, or liquid poloxamers, whichwill generally only form alloys with closely related copolymers, suchthat no advantage is to be gained by the mixing. Adjustment of the massratio between non-random polymer and random copolymer can be used toproduce compositions of varying hardness and viscosity. Forcompositions, the mass ratio (block AOC: random AOC) may be 1:199 to199:1. A mass ratio of about 2:98 with 22K random AOC is no longer aflowable liquid, while a mass ratio of about 1:19 with 22K random AOC isa solid. The mass ratio may be at least about 1:4, about 1:3, or about1:2; the mass ratio may also be not more than about 2:1, about 3:1, orabout 4:1. The compositions may be further described by intermediateranges using the aforementioned upper and lower limits.

The mechanical properties of most polymers need to be adjusted by theinclusion of plasiticizers to make them suited to their intended use.Plasticizers are used to make the polymer softer, more malleable orductile, and less brittle, and must be miscible with the polymer tofulfill this function. Most plasticizers are small molecules, which bytheir nature, are often toxic or non-biocompatible and easily releasedfrom the polymer. A polymeric plasticizer would be very valuable formany applications, especially one that was biocompatible, not toxic, notmetabolized, and rapidly eliminated. Polymeric plasticizers for solidalkylene oxide polymers and copolymers have not previously beendescribed. Our extensive efforts to find a suitable biocompatiblematerial that could be used as a softener or plasticizer eventually ledto the identification of a specific molecular weight range of random AOCwhich forms compatible or miscible blends (i.e., polymer alloys) withblock AOC and AOH (see Tables). The finding that a liquid random AOCcould be used in combination with a solid non-random PAO to form a novelpolymer alloy with commercial utility was unanticipated and has not, toour knowledge, previously been described.

Polymer alloys can be made with handling characteristics that range froma grease-like consistency to a hard wax. The different levels ofmalleability and plasticity can be achieved largely by altering thechoice of components and their proportions as outlined in the Examplesand Tables. The various other embodiments are made in a similar manner.The solid AOH or block AOC copolymer component is normally not dissolvedby the liquid random AOC component at room temperature. A polymer alloycan be made, however, as follows: The solid component is brought to itsmolten state by the application of heat. The random AOC component isheated to the same temperature, and the two components are thoroughlymixed by stirring in the molten state. Upon cooling, the AOC alloy isformed. Altering the cooling rate can also be used to adjust thehandling characteristics and structure of the AOC alloy.

A non-flowable composition can be made with a relatively small amount ofthe solid block AOC component. As an example, an alloy containing 2parts by weight of the solid poloxamer 188 to 98 parts of the liquid 22Krandom AOC does not flow at room temperature (see Tables). On the otherhand, a hydrogel made from poloxamer 188 and water would require 30% ofthe solid to form a non-flowable gel at 37° C., but would still flow atlower temperatures.

The compositions may alternatively be formulated in solid or liquid form(e.g., milling, agitating, kneading, or stirring), but heating of thecomposition is preferred to achieve uniformity with solid or viscousforms. The composition may be sterilized by standard techniques such asautoclaving or irradiation. It may be molded by hand; applied with abrush, flat or shaped rod, or syringe; formed into a bar or stick; orimplanted/placed in the body. A device may be coated or a bioactiveagent mixed with excipient. Malleability, thermoplasticity, andviscosity may be measured by methods known in the art. Similarly,bio-compatibility and non-toxicity may be assayed by methods known inthe art.

In one preferred embodiment, the composition is made by mixing a 1:1ratio by weight mixture of a block AOC that is a solid at roomtemperature, such as poloxamer 188, with a random AOC, such as 22Krandom AOC, that is a liquid at room temperature. However, a range ofphysical properties for the AOC alloy can be created depending on theirintended use (see Tables).

In its anhydrous state, poloxamer 407 (PLURONIC® F127) is a hard solid,and it is available as a gritty powder or in flake form and as such isnot very useful. Adding even small amounts of the 22K random AOC softensthe hard material, producing a homogeneous wax or soap-like materialwith improved handling characteristics, but with the surfactant andother properties similar to those of the original poloxamer 407. Withincreasing concentrations of the random AOC, the composition becomesmore malleable.

Conversely, 22K random AOC is a flowable, viscous liquid at roomtemperature. By addition of as little as 2% (w/w) of poloxamer 188, apolymer alloy is formed which handles like a greasy solid and does notflow at room temperature.

It is anticipated that other synthetic AOC will be developed and becomecommercially available. It may be feasible, for example, to makecompounds containing AO chains that do not fall clearly into the scopeof the claims. It is conceivable that a high molecular weight compoundthat is a liquid at room temperature could be made that would falloutside the strict classification of a random AOC, or that a AOCessentially solid compound may not be strictly composed of blocks. It isentirely conceivable that a PAO copolymer could be made to containsections of a block copolymer and a random copolymer. Such equivalentsshould be included within the scope of protection.

Medical Utilities

Some embodiments relate to an adhesive material that can be used inorthopedic surgery, dentistry, reconstruction, spinal and craniofacialsurgery, and other surgical applications because of its improvedproperties. Numerous uses include bone hemostasis agent or as anadhesive agent that can, for example, facilitate the adherence of ascrew to the blade of a screwdriver. In one preferred embodiment, apolymer alloy is made using a 1:1 ratio of NF grade poloxamer 407(PLURONIC® F127NF) and 22K random AOC. The handling characteristics ofthis formulation make it especially useful as a bone hemostasis agent,as the sticky, cohesive wax adheres well to bone, even when the surfaceof the bone is wet. In contrast to the prior art, preferred embodimentsprovide a biocompatible, substantially non-toxic, stable (i.e.,non-metabolizable and readily eliminated) polymer alloy with superiorhandling characteristics.

Porous implant materials are useful for the repair or reconstruction ofthe bony skeleton. Implants can be used to fill bony defects, or theycan be to augment or replace bone or cartilage in humans or in animals.Porous implants with a pore size of 60 microns or greater exhibit tissueingrowth into their pores. Collagen is deposited within the pores andforms a highly static complex, which is resistant to infection andexposure. For a porous composition to be effective as an implantmaterial, it must fulfill four criteria: (1) biocompatibility, (2) thepores must be large enough to allow for tissue ingrowth, (3) the poresmust interconnect, and (4) the structure of the implant must be bothpermanent and rigid enough to maintain the porous framework underconditions encountered at the implanted site, To be useful, the materialmust also be sufficiently easy to use in a clinical setting. It is alsodesirable for the material to be non-toxic, have a relatively long shelflife, be relatively economic, and have good handling characteristics.There is a need to improvement the handling characteristic and to add aresorbable composition to fill or cover the pores. Filling or coveringthe pores would allow the implant to glide through tissue planes andwould keep debris from entering the implant.

Therefore, a further object is to create a porous implant whose poresare filled or covered with a resorbable substance.

Porous implants used in humans and animals are made by sintering solidparticles such as polyethylene, PMMA, or titanium; or they are adaptedfrom naturally substances such as coral in the case of porous corallinehydroxyapatite. Polyethylene, a biologically inert material, hasnumerous applications in surgery. It is a straight-chain hydrocarbonsynthesized by the polymerization of ethylene. Hydroxyapatite andtricalcium phosphate are similar in composition to the major mineralcomponent of bone and may be resorbed or remodeled, depending on theirformulation. Methacrylate- and silicone-containing particles are notpreferred for use.

Placement of porous implants into one or more bone defects is a commonsurgical procedure. Implant materials that allow for bone to grow intothe pores are considered to be osteoconductive. Implants that have abioactive component that induce bone formation, such as implants madefrom a bone removed from a different location, are considered to beosteoinductive. In the event that it is desirable that native boneeventually replaces the implant, material that can be remodeled by thebody may be preferable. In certain clinical situations, such as a defectin the adult human cranium, the bone is not expected to grow, and anon-resorbable formulation is preferable. Studies have shown that in thecraniofacial skeleton, a number of commonly used solid implants causebone resorption adjacent to the site of implantation. Porous implantsmay not have the same effect.

The majority of porous implants that allow for tissue in growth aregrossly solid structures with a microporous structure. To be clinicallyuseful, they often need to be sculpted by the surgeon into their desiredform. The microporous structure of the implant can cause the implant toadhere to tissue, much like a piece of VELCRO hook-and-loop fastener,making the implant placement difficult. Debris deposition into the poresis another undesirable drawback to the use of porous implants. Todecrease the risk of bacterial infection, the implant may be soaked inan antibiotic solution prior to use.

An implant whose pores are filled with a biocompatible excipient wouldbe an improvement over the implants in current clinical use. Temporarilyfilling those pores until such time as in growth of tissue occurs wouldeliminate the accumulation of debris within the implant and coulddecrease the incidence of bacterial infection. Temporarily filling thepores using an appropriate excipient would also improve its handlingcharacteristics to make the implant more lubricious and less damaging totissue, thus allowing the implant to slide along tissue planes duringsurgical placement. The appropriate excipient could then also becomeadherent in the presence of body fluids and lessen the incidence ofmalpositioning that can occur after implant placement. The biocompatibleexcipient could also serve as a carrier for therapeutic products. Forexample, chemical compounds could be released over time as the excipientis resorbed.

A preferred carrier or excipient should be biocompatible, non-toxic,non-metabolizable, readily eliminated, relatively economic, and havegood handling characteristics. The composition may allow an implant tobe lubricious to glide along tissue planes, but it should also enablethe implant to become adherent to surrounding structures when its finalposition is attained. Cohesion may be used to temporarily hold tissuetogether until more permanent attachments may be made. An anhydrousformulation might increase the half-life of a biological agent andreduce the risk of contamination.

In a preferred embodiment, water-soluble bone wax is applied to thesurface of a porous implant, for example a coralline, poroushydroxyapatite implant, which would cause the implant to become slipperywhen in contact with tissue fluids, thus facilitating the placement ofthe implant by reducing the adherence of the surrounding soft tissue.

In another preferred embodiment, a porous implant can be made so thatits pores are largely or completely filled with a resorbable polymer.This could be achieved, for example, by placing a porous polyethyleneimplant into a molten polymer composition under a vacuum, and thenallowing it to cool. The resulting implant would glide along tissueplanes, it would remain flexible, and it would be resistant to havingdebris collect within its pores. Once implanted, vascular and softtissue ingrowth into the pores of the implant could occur as the polymeralloy is resorbed.

The prior art teaches the use of random AOC as lubricants with a highaffinity for metal surfaces. But random AOC are liquids which, likeoils, will flow away from surfaces unless continuously replaced. Toformulate a grease which will remain in place for lubricating bearingsand the like, manufacturers of such products will often combine an AOCor AO homopolymer base stock with an ionic soap, usually lithium,calcium, or sodium based. There is an unmet need for a non-flowable,non-ionic, non-corrosive, and completely water-soluble grease-likelubricant, particularly one that is biocompatible and suitable for usein medicine and surgery. In another embodiment, a water-solublecomposition is used as a non-flowable, non-corrosive, and water-solublelubricant.

During surgery, lubrication of instruments or other devices is usuallylimited to physiological saline and the patient's own fluids. Use oflubricious substances derived from human or animal sources risks animmune response and the transmission of infectious agents. There is aneed for a safe, biocompatible, inexpensive carrier that could be usedas a surgical lubricant that can be applied when needed. Such alubricant could decrease tissue injury and/or improve the handlingcharacteristics of devices as they are passed through tissue. Examplesof injuries caused by surgical instruments are abrasive tissue burnscaused by endoscopic instruments as they are moved along narrow tissueplanes. Surgical implants, such as those made from porous polyethylene,are especially difficult to pass along tissue planes, since soft tissuetends to adhere to these implants. Breast implants, especially thosewith a textured surface that are placed through small, remote incisions,can be very difficult to place without sufficient lubrication, Thus, thecomposition may be used as a carrier for devices (e.g., implants,instruments) to ease insertion.

In one embodiment, the AOC alloy can be used as a lubricant and/orprotectant. For example, a polymer alloy made using a 1:19 ratio of NFgrade poloxamer 407 (PLURONIC® F127NF) and 22K random AOC could beapplied to the surface of a steel surgical instrument, prior to theinstrument being used in surgery. The polymer alloy would serve as aprotectant, and would have the advantage over prior art in that it isnot liquid, therefore it would not flow, nor would it be absorbed bycloth that typically comes in contact with surgical instruments. Itwould have the added advantage of being completely water-soluble andnon-toxic. Once used in surgery, in the presence of tissue fluids, thesurface of the instrument would become lubricious, which would enhancethe ability of the instrument to glide along tissue surfaces.

Another embodiment is an adhesive material comprised of a matrix (e.g.,PEO, or a block AOC copolymer or a random AOC copolymer, or acombination thereof) combined with a porous or solid filler for use insurgery.

In a number of clinical applications, it is advantageous to construct aporous structure by placing an aggregate of solid particles or granulesthat become fixed in into their desired location by the in growth ofsoft tissue into the spaces between the particles. Allograft bone is asubstitute source for solid particles. It is readily available andprecludes the surgical complications and patient morbidity associatedwith autologous bone as noted above. Allograft bone may be considered acollagen fiber reinforced hydroxyapatite matrix containing active bonemorphogenic proteins (BMP) and can be provided in a sterile form. Themineral component may be removed from bone to form a demineralized bonematrix (DBM). Such DBM is naturally both osteoinductive andosteoconductive. Once surgically implanted, DBM is fully incorporated inthe patient's tissue and it has been used in bone surgery to fillosseous defects. DBM is usually available in a lyophilized orfreeze-dried and sterile form to provide for extended shelf life. TheDBM in this form is usually very coarse and dry, and is difficult tomanipulate by the surgeon. It is known that DBM can be supplied in amatrix of low molecular weight solvents, but these are know to be toxicto the surrounding tissue, and they form a runny composition.

Therefore, one embodiment is to use the composition as a matrix for DBM.As an example, a composition containing a 1:2 mass ratio of poloxamer407 (PLURONIC® F127NF) and 22K random AOC can be used. The resultant DBMputty has superior handling characteristics and will adhere DBM to theintended site, it is non-toxic to surrounding tissue, and it contains nowater that could inactivate the bone morphogenic proteins in the DBM.

Inorganic materials can also provide a matrix for new bone to grow atthe surgical site. These inorganic materials include hydroxyapatiteobtained from sea coral or derived synthetically. Either form may bemixed with the patient's blood and/or bone marrow. Hydroxyapatitegranules may be used as bone inlays or onlays. The granules can be mixedwith microfibrillar collagen and blood from the patient. Although themixture is termed a “paste” herein, it may also be described as a gel,putty, or slurry depending on its handling characteristics.

Particles with sizes (i.e., the largest dimension) in the range fromabout 35 microns to about 500 microns (or about 50 microns to about 150microns) are desirable to minimize the possibility of particle migrationby phagocytosis and to facilitate injectability. Phagocytosis occurswhere smaller particles on the order of 15 microns or less becomeengulfed by the cells and removed by the lymphatic system from the sitewhere the augmentation material has been introduced into the tissues,generally by injection. At the lower end, particles greater than 15microns (typically 35 microns or above) are too large to bephagocytosed, and can be easily separated by known sizing techniques(e.g., filtration, gel exclusion, molecular sieving). For a populationof substantially spherical particles, the diameter may range from about35 microns to about 500 microns for at least the majority of thepopulation. Thus, it is relatively simple to produce narrow orequivalent particle size ranges that are desirable for use.

Particles may comprise at least about 10% (v/v), at least about 25%(v/v), not more than about 40% (v/v), not more than about 64% (v/v), orcombinations thereof. The composition may be kneaded or otherwise workedto obtain a homogeneous distribution of particles within thecomposition. Such working is avoided, however, if a non-homogeneousdistribution is desired and different compositions may even be laminatedtogether.

As an example, polyethylene particles ranging in size from 50 to 300microns are blended with a composition containing a 1:2 ratio ofpoloxamer 407 (PLURONIC® F127NF) and 22K random AOC. The resultantpolymer putty can be used to fill cranial defects. The matrix performstwo important tasks: it forms a cohesive putty and serves to adhere theparticles to the intended site of implantation. In this regard, thecomposition is superior to the prior art.

Excipients are biologically inactive substances that are associatedwith, often in combination, drugs, devices, and other therapeutic agentsto make a therapeutic product. They may be classified by the function(s)they perform as binders, disintegrants, fillers, diluents, suspendingagents, dispersing agents, lubricants, flow enhancers, softeners,plasticizers, and coatings. Although biologically inert, they may becritical and essential components of a therapeutic product. They mightbe used to reduce lability of a bioactive agent, enhancebioavailability, and/or control the location and rate of release of thebioactive agent. They also may be required to deliver a pharmaceuticalformulation by a desired route, whether oral, parenteral, enteral, ortopical and, if appropriate, to enhance the appearance and palatabilityof the product. In many therapeutic products, excipients make up thebulk of the total dosage form. The excipient can be sterilized prior toformulation by autoclaving or irradiation, or the formulation may besterilized as part of its production. In addition, a vehicle may beincluded in the therapeutic product. It may be water, another aqueoussolution with buffer and/or physiological salts, non-aqueous solution,emulsion, or suspension. The device may be a filler, anchor, catheter,implant, plate, prosthesis, screw, suture, surgical instrument, or thelike; it may be made from bone (e.g., chips or powder) or a derivativethereof (e.g., demineralized bone), ceramic (e.g., calcium saltespecially hydroxyapatite), glass, polyethylene, or metal (e.g.,stainless steel, titanium). The drug may be a bone growth factor ormorphogenic protein, hormone, other protein, nucleic acid (e.g., DNA,RNA, analogs or mixtures thereof), analgesic or anesthetic, antibiotic,antiseptic, narcotic, steroidal or nonsteroidal anti-inflammatory agent,or the like.

The compositions are also well suited as carriers or excipients fordelivery of bioactive agents, medical/surgical devices (e.g., implantsand instruments), and other therapeutic (e.g., non-polymeric) products.Articles may be coated with carrier or chemicals may be mixed withexcipient. Sterilization may be performed in an autoclave or byirradiation for use in vivo.

Bone morphogenic proteins (BMP) and TGF-beta are two examples ofbioactive substances. Other differentiation factors, stem cell factors,antibiotics, antibodies, antigens, chemotherapeutics,cytokines/chemokines, enzymes and their substrates (e.g., activators,inhibitors, or reactants), receptors (especially secreted forms andmimetics thereof) or their ligands (e.g., agonists or antagonists),signaling molecules (e.g., mediators of a signal transduction pathway,agonists or antagonists thereof) may be formulated in a composition withthe composition.

For use as a carrier or excipient, the attributes of beingbiocompatible, substantially non-toxic, simple to manufacture, andreadily eliminated by a human or animal are important. In addition, thecomposition may solubilize hydrophobic compounds and thereby releasethem into solution. An anhydrous formulation has the benefit ofproviding a stable excipient to those bioactive agents that are labilein an aqueous environment. Furthermore, if water is present, thecomposition serves to bind the water to make it unavailable to interactwith the bioactive agent. Water-insoluble compounds may be incorporatedinto a polymer composition, and then administered to a subject. There isno prior art known to have these attributes.

Examples of a carrier or excipient are (1) polymer alloy containing a1:2 mass ratio of poloxamer 407 (PLURONIC® F127NF) to 22K random AOC and(2) polymer alloy containing a 1:1 mass ratio of poloxamer 188(PLURONIC® F68NF) and 22K random AOC.

Certain vectors, such as viruses and infectious particles, likewise arein need of an excipient that is free of water. One embodiment is toprovide an excipient for biological vectors that is biocompatible,substantially non-toxic, and may be formulated to contain no water. Suchan excipient has utility in delivering vectors to cells, tissue, organs,animals, and plants.

Joints of some surgical instruments (e.g., scissors and clamps)typically need to be cleaned and the joints need lubrication. Suchinstruments can be dipped in instrument milk prior to their use insurgery. Thus, in addition to use as a detergent, the composition may beused as a lubricant. The effectiveness of a composition as instrumentmilk may be enhanced because of its biocompatibility, flowability,substantial non-toxicity, and water solubility.

As described above, a composition may be used as excipient for drugdelivery or in the manufacture of other bioactive agent-containingcompositions to deliver such compounds to a subject though a variety ofroutes, including percutaneous, enteric, intranasal or respiratory,topical, and through mucous membranes (e.g., rectum). When ingestedorally in sufficient quantity, the composition may have biologicalactivity of its own due to the ability to draw water into thegastrointestinal tract and act as a laxative.

Open wounds, particularly those that are infected or have a tendency toseep fluid, continue to be a difficult management problem for healthcare providers. The aims of wound care management in these situationsinclude keeping the wound moist, thus optimizing the conditions for thewound to heal; removing excess fluid and debris from the wound; andminimizing or treating infections. It would be advantageous for acomponent of the wound dressing to remain moist, have the ability toremove or absorb excess fluid, and be formulated to include anantimicrobial agent. Thus, one embodiment provides such a substance forwound care.

There are a variety of topical formulations encompassing creams, gels,and ointments, including sun blocks and wound dressings. There is anunmet need for a lubricious component which absorbs water and is thusbeneficial in treating seeping wounds and stasis ulcers. The compositionmay be packaged in a bottle or tube, applied to the wound, and thenoptionally covered by a occlusive or non-occlusive dressing.Alternatively, it may be prepackaged with the dressing under asepticconditions.

Therefore, in some embodiments, the composition may be used as alaxative or wound dressing.

Nonmedical Utilities

Wax is an organic, plastic-like substance that is solid at 25° C. andmelts to a liquid when heated. Because wax is plastic in nature, itdeforms under pressure without the application of heat. The term “wax”is applied to a large number of chemically different compounds, and ithas come to include compounds that are soluble in water. These waxes aresaid to have the properties of aqueous dispersion. U.S. Pat. No.6,554,052 teaches the use of a water-soluble wax to decease the amountof precious metal in the production of jewelry and its utility in the‘lost-wax’ casting process. There is a need for improvement in thehandling characteristics and the ease of manufacture of water-solublewaxes.

In one embodiment, the composition is used as a wax.

There is a need to formulate crayons and pastels to be non-toxic andwashable with water. U.S. Pat. No. 4,978,390 teaches a composition inthe form of a crayon or marking pencil lead which is washable fromfabrics, wallpaper and painted surfaces. A preferred embodiment of thecomposition contains an epoxide derivative of a poly(ethylene glycol)resin. Such a composition has the disadvantage of leaving residue afterthe application of water. There is a need for a simple, inexpensive,substantially non-toxic, water-soluble crayon.

Appropriate compositions (e.g., a polymer alloy of about three parts byweight of poloxamer 338 and one part by weight of 22K random AOC)produce a medium-hard wax that is not brittle and which can be rubbedonto a surface such as paper, without flaking or fracturing, like aregular wax crayon. A wide range of harmless dyes can be used to colorthe composition, including those presently used to color the regulartypes of children's wax crayons, simply by mixing with the moltenpolymer mixture prior to casting the material into anappropriately-shaped crayon mold. The crayon thus formed is made fromonly two inexpensive components plus dye, is non-toxic, and has theutility of a regular crayon for drawing but is fully water soluble. Whenadded as a fine powder to the molten composition, many hydrophilic dyes(e.g., methylene blue) are dispersed but not dissolved. Crayonsformulated in this way can have a pale, slightly mottled appearance. Inuse, these crayons only faintly mark the paper. However, since thecrayon wax is water soluble, subsequent application of a small quantityof water to the paper results in the development of bright, saturatedcolors often quite different from the apparent color of the crayon used.Thus, these compositions have utility as novel art materials. A furtherobvious benefit of the water-soluble crayon is the simplicity ofclean-up if the crayon is misused. Washable dyes and other colorants areused as pigment.

In another embodiment, the composition is used to as a carrier for acolor pigment that could be used in the manufacture of washable crayons.

Poloxamers and other detergents have been used to sterilize surfaces andmaterials, Such agents are usually in powder or flake form. There is aneed for a non-ionic soap, detergent, or stain remover which has theutility of poloxamers, including the ability to perform in solutionswith a high mineral content (e.g., hard water) or solutions of highsalinity (e.g., such as brackish water or seawater), and can be providedin an advantageous physical form with improved handling characteristics,such as a solid bar or rub-on stick. Here, the composition provides thesurface active functionality of a non-ionic detergent in a convenient,easy to use form.

The surfactant properties of the composition are of benefit when anon-ionic cleanser or stain remover is needed. Such a cleanser is ofbenefit in that it is environmentally safe, does not leave soap scum,and will perform in hard water and saltwater environments. As anexample, an alloy of about of 60% by weight of poloxamer 188 and 40% byweight of 22K random AOC can be melted and cast into a bar form,preferably similar to the shape of a standard bar of soap. Theformulation can be used as a cleanser bar, and has an appearance verysimilar to glycerin soap, which can be further enhanced by includingother cleansing agents, boosters, colorants, fragrances, andmoisturizers in the formulation if so desired. The main value of thisembodiment is that the non-ionic surfactant property of poloxamer 188,which in its regular form is a hard white granular material, can beapplied to tasks for which it has not been previously used, such as handwashing, in a familiar, simple and convenient bar form. Other poloxamersor similar block copolymers can also be used in place of the poloxamer188. The non-ionic soap bar is effective for use as a mechanic's handcleaner for removing oily and greasy grime, will work with hard waterwithout producing soap scum, and can be used in saltwater.

Aqueous release agents are used in applications such as molding. Thereis a need for a non-toxic, non-corrosive, water-soluble, non-flowable,and inexpensive release agent that will adhere to a surface but willrelease on demand, such as when placed into an aqueous environment.

In one embodiment, a water-soluble composition is used as an aqueousrelease agent.

For use as a water-soluble, non-petroleum-based, synthetic lubricant,the composition can be formulated in any number of different grades froma hard wax to a soft grease simply by varying the proportions of thecomponents. A blend of about 30% (w/w) of a random AOC, such as 22Krandom AOC, and about 70% block AOC, such as poloxamer 188, cast into asimple stick form (e.g., in a retractable tube) provides a medium-hardlubricant stick that can be rubbed on where needed or applied safelydirectly to moving surfaces, cutting tools (e.g., saw blades, drillbits, planing machines) or parts of machinery. The water-soluble,non-oily nature of the composition is useful to prevent damage orstaining when machining delicate materials or wood, and simplifies cleanup. The composition has further advantages when used as a metallubricant because the random AOC component is attracted to, and platesout on, hot metal surfaces. The non-corrosive properties are also abenefit for metal working applications.

A medium blend of about 40% of 22K random AOC, about 60% of poloxamer188 can be used in bar or stick form as a rub-on lubricant for theunderside of skis, snowboards and the like. For this application, thelack of toxicity, proven environmental safety, and non-corrosive natureof the component materials are especially advantageous.

As an example of a grease, 95% to 98% of 22K random AOC and 2% to 5% ofpoloxamer 188 were blended to provide a stiff to soft semi-solid grease,which does not flow under gravity at room temperature. It is a usefulgrease alternative, especially for lubricating metal parts, because itis less labile than natural or petroleum-based oils, with the additionalbenefits of being water soluble, biocompatible, and substantiallynon-toxic. With very low amounts of block AOC, the blend may become aviscous, somewhat sticky, oily liquid which has utility as a lubricant.

Any lubricant composition can also be used as a carrier for otherfriction modifiers (TEFLON particles, colloids, etc.), includingpotentially useful friction modifiers that are not readily oil soluble.

EXAMPLES

The following examples more particularly describe the invention but areintended for illustrative purposes only, since modifications andvariations will be apparent to those skilled in the art.

Example 1 Characterization of Polymer Compositions

Specific characterization of various embodiments can be ascertained byusing various specialized techniques (e.g., high-sensitivitydifferential scanning calorimetry), which can be used to probe theprecise nature of the alloy and the interaction between the componentmolecules. In particular, the miscibility may be confirmed byalterations in the glass transition temperature (Tg) of the alloyrelative to the Tg of the individual components, if the Tgs of theindividual components are sufficiently different. However, suchmeasurements on polymer mixtures can be very difficult to make andinterpret, even by experts in the field. If good results are obtainedthey are often strictly limited to the precise composition, volumefraction and temperature at which the measurement was made and, evenwith the best theoretical analysis, these data may have littlepredictive value for other combinations of polymers, even with onlyslight differences in the molecular weight or structure. Thus, it provedmore expedient to screen the polymer blends by direct observation bothmacroscopically and microscopically, to determine which combinationsprovides the desired combination physical properties, and to determinewhether the polymers are compatible or miscible on the microscopicscale, as follows.

Non-random AOH or AOC and random AOC were blended together in variousproportions. Appropriate amounts (w/w) of each polymer were placed in aglass container to prepare 10 g of polymer mixture, and heated in amicrowave for 60 to 90 seconds to melt the solid component (the time wasvaried as necessary for the polymer mixture to reach approx 80° C.).After thorough mixing, the samples were centrifuged at 500 g for 2minutes to eliminate any air bubbles. All samples had a water-clearappearance in the molten state at 80° C.

For macroscopic evaluation, the molten polymer blends were reheated to80° C. and cast into small bars by pouring into individual aluminummolds of 2 inch×0.75 inch×0.1 inch deep, and held at 4° C. until fullyset (less than 5 min). The appearance and mechanical properties of eachsample were evaluated visually and by hand molding in a mannersimulating some of the intended applications of the polymer alloy. Forthe microscopic testing, 15 μl to 20 μl of the melt was pipetted onto aglass microscope slide on a thermostatically controlled hotplate. Acoverslip was placed on top of the melt and slight pressure applied tocause the polymer blend to flow just to the edges of the 25 mm×25 mmcoverslip, to form a consistent thin layer. The slide was then removedfrom the hotplate and examined under the microscope. Copolymerspherulites or immiscible blends were photographed at 10× magnification.A differential interference contrast system (crossed polarizers) wasused to enhance the characteristic birefringence pattern (Maltese cross)displayed by spherulite crystals.

Three random copolymers were evaluated: a three-branched 22K g/molrandom AOC (22K random AOC) with an EO:PO ratio of 1:1 (BASF Pluracol®V-10); a linear 12K g/mol random AOC (12K random AOC) with an EO:POratio of 3:1 (Sigma-Aldrich #43,820-0), and a linear 3.9K g/mol randomAOC (3.9K random AOC) with an EO:PO ratio of 1:1 (Dow UCON 50-HB-5100).The non-random copolymers were selected from a range of Pluronic® blockcopolymers (F68, F88, F98, F108, F87, F127) and PEO (homopolymer)fractions of various molecular weights (about 1.5K, 2K, 3.5K, 5K, 7.5K,12K, 20K, and 35K g/mol).

The macroscopic properties of the polymer combinations are described inthe Tables, including both descriptive data and a semi-quantitativeranking for each property of interest, for which the 1:1 alloy of F68and V-10 was used as a reference point. The data show the ranges ofcompatibility for different types and molecular masses of poloxamers andPEO molecules with each of the three random copolymers.

For the 22K random copolymer, macroscopically compatible blends could bemade with F68 (poloxamer 188) over a wide range of proportions, from 2%to 98%, with no evidence of incompatibility. The blends with a lowproportion of F68 (2% and 5% in Tables) resembled clear, colorlessgreases, while the others were waxy solids, ranging from very soft tovery hard, similar in appearance to other forms of wax (e.g., paraffinwax or candle wax). The handling properties of the alloys tracked thepolymer proportions closely, with hardness increasing and malleabilityand ductility decreasing with increasing F68 content over the range from2% to 80%. Mixtures of 22K random AOC with F88, F98, F108, F87 and F127were also evaluated in selected proportions. Relative to the F68compositions, each of the other block copolymers conferred slightlydifferent and potentially useful characteristics to the composition Forexample, a 50:50 mass ratio of F127 block copolymer to 22K random AOCproduces an alloy that was softer, more malleable, and tackier than asimilar composition of F68 block copolymer and 22K random AOC, and hadan attractive white opaque appearance while the F68 composition wasclear. Other differences are apparent from the data in the Tables.

The compatibility of PEO in combination with 22K random AOC was afunction of the PEO molecular mass. Thus, macroscopically compatibleblends were obtained for PEO of 1.5K g/mol to 5K g/mol, but 7.5K g/molwas minimally or not compatible and 12K g/mol PEO was clearlyincompatible with the 22K random AOC, as indicated by a grainy textureand lack of cohesion of the blend. The compatible PEO compositions weregenerally similar to the block copolymer compositions, but tended to besofter and more ductile, and to have a different “feel”, i.e., more oilyto the touch and a gum-like tackiness.

The 12K random AOC random copolymer also formed alloys with the sameblock copolymers and PEO homopolymers (2K, 3.5K, and 5K) and wasincompatible with PEO samples of 12K and above. The 12K random AOCalloys were almost identical in terms of mechanical properties andappearance with the equivalent 22K random AOC compositions. In contrast,the lower molecular weight random EO:PO copolymer, 3.9K random AOC, wasnot compatible with any of the block copolymers or homopolymersevaluated in the study: although apparently completely miscible at 80°C., the blended polymers separated on cooling, forming a two-phasesystem of hard crystalline grains of the non-random polymer in a stickyor liquid carrier (predominantly the 3.9K random AOC). These resultsindicate that higher molecular weight random AOC are necessary to formcompatible blends with block AOC and PEO: the threshold presumably liesbetween about 4K g/mol and about 12K g/mol.

Although most of the AOC polymer combinations formed macroscopicallyhomogeneous materials, the microscopic studies were necessary to provideconfirmation of the compatibility of the polymer phases. FIG. 1 showslow power (125×) views of alloys of 22K random AOC and F68, inproportions from 2% (w/w) to 98% (w/w) after cooling. Looking first atthe 20% (w/w) to 60% (w/w) samples, each image is very similar, witheach spherulite crystal extending through the material to meet adjacentspherulites along very precise boundaries without any gaps or spaces.From 2% (w/w) to 10% (w/w) F68 blends, the spherulites are less distinctdue to the lower amount of the crystal-line F68, but it is apparent thatthe size of the spherulites is the same and again, there are no gaps orother defects. Above 60% (w/w) F68, there is an increase in thespherulite size, and lines (dark under the microscope) appear betweenthe region between the spherulites. Observation of the polymer blendwhile cooling revealed that these lines are in fact negative defectsthat appear suddenly in the liquid phase between the advancingspherulite boundaries, presumably due to the sudden nucleation of a gasbubble under the negative pressure resulting from the contraction of thematerial. These bubble defects appear to be the cause of the increasedwhiteness and opacity of the alloys with increasing F68 content, Theregularity of the spherulite structures and the absence of 22K randomAOC-filled spaces between the spherulites indicates that the material iseffectively a single phase, with the two polymers completely andintimately associated with each other at least on the micrometer level.

FIG. 2 shows a 1:1 mass ratio of random copolymer and non-randompolymer. FIGS. 2A-2B are from compatible alloys—note the even spherulitepattern, and the absence of any defects. FIGS. 2C-2E are examples ofincompatible and immiscible compositions. Several distinct phases areseen—some large spherulite crystal domains of the PEO interspersed withlarge clear globular regions of the random copolymer, within which areadditional smaller droplets of PEO which have crystallized into shapescorresponding to the interface of the phase-separated droplet.

Thus, we have defined the range of compatibility for combinations ofrandom and non-random alkylene oxide polymers, making possible thecreation of polymer compositions with a range of very useful materialproperties. The results further indicate how to select the precisetypes, molecular masses, and proportions of the component polymers totailor the material properties of the composition to satisfy the desiredspecifications. The discovery of compatible combinations of these typesof polymers, and identification of appropriate molecular weight rangesfor the component polymers is novel and unexpected, and is not taught byany of the prior art.

Example 2 Polymer Composition for Bone Hemostasis

A preferred composition with utility as a bone hemostasis agent may beproduced in the following manner: Equal quantities by weight of NF gradepoloxamer 188 (PLURONIC® F68NF) and 22K random AOC are sealed in aheat-resistant glass container and heated to a temperature of 80° C. inan oven. The contents of the flask is stirred for a period of 8 hours at80° C. The liquid composition is allowed to remain undisturbed foranother 16 hours at 80° C. to allow air bubbles to escape from withinthe liquid. The liquid is then dispensed directly into TEFLON coatedmetal molds maintained at a temperature of 80° C. The molds are cooledto 4° C. for 15 minutes. The solid polymer composition is removed andplaced into individual foil packets lined with a polyethylene coating.These packets are then placed into pouched appropriate for packagingsterile implantable devices. The product is sterilized using anappropriate dose of plasma radiation.

A study was performed comparing the long-term effects of AOC wax andcommercially available beeswax in paired cranial defects in the adultrat. Two defects 4 mm in diameter were hand cut using a dental drillthrough the parietal bones on either side of the midline in 10Sprague-Dawley rats. The materials used were in the shape of disks 4 mmin diameter and 1.0 mm thick, and were either AOC wax comprised of equalquantities by weight of NF-grade poloxamer 188 (PLURONIC® F68NF) and 22Krandom AOC, or beeswax (Bonewax, Ethicon, Inc.). Both materials wereimplanted into each rat. At surgery, the two materials exhibited nodifference in their handling characteristics and hemostatic effects.Animals were sacrificed at 7 days, 30 days, 60 days, and 90 days. Ongross inspection, the beeswax remained present in each animal and therewas no remaining AOC wax. There were no visible ill effects of the AOCwax. After formalin fixation, plain radiographs (16 inch distance, 50 kVfor 0.1 sec) were obtained. No ill effects of the AOC wax on bonehealing could be seen upon examination of the radiographic images. Thebones specimens were then decalcified in 5% acetic acid for 7 days,embedded in paraffin wax and sectioned for hematoxylin and eosin (H & E)staining. Upon microscopic examination of the specimens, there was noevidence of deleterious effects of the AOC wax on bone healing, thelocal tissue or the underlying brain.

Example 3 Non-Toxicity of Polymer Composition

The biocompatibility of the composition was demonstrated by assessingintracutaneous reactivity, systemic toxicity, cytotoxicity, hemolysis,mutagenicity, and the potential for chromosomal aberration. Thecomposition used for all tests was composed of equal quantities byweight of NF-grade poloxamer 188 (PLURONIC® F68NF) and 22K random AOC.

The composition was evaluated for intracutaneous reactivity to test forpotential irritation and sensitization. A 0.2 ml dose of the materialwas injected by the intracutaneous route into five separate sites on thebacks of rabbits, along with controls. Observations for erythema andedema were conducted at 24, 48, and 72 hours after injection showed noevidence of irritation. The primary irritation index characterizationfor the composition was negligible.

The composition was evaluated for systemic toxicity in accordance to theguidelines of the United States Pharmacopoeia and the InternationalOrganization for Standardization (ISO) 10993. A single 50 ml/kg bodyweight dose of the material was injected into mice by the intravenousroute. The animals were observed at timed intervals for 7 days withoutany evidence of systemic toxicity.

Cytotoxicity was assessed using an in vitro biocompatibility study basedon ISO 10993. A solution was prepared supplemented with 5% serum and 2%antibiotics, placed over confluent monolayers of L-929 mouse fibroblastcells propagated in 5% CO₂, and incubated at 37° C. in the presence of5% CO₂ for 48 hours. The monolayers were examined microscopically at 48hours and showed no evidence of a change in cell morphology, cell lysis,or cell toxicity.

The composition was also tested in vitro to see if it would causehemolysis (lysis of red blood cells) when in contact with human redblood cells. The material was incubated in a solution of human red bloodcells for 4 hours. After incubation, no released hemoglobin wasdetected, which indicated an absence of hemolysis.

The potential carcinogenicity of the composition was ascertained using abacterial reverse mutation study in which mutagenic potential wasassessed in histidine-dependent strains of bacteria. The geneticallyaltered S. typhimurium strains TA98, TA100, TA1535, and TA1537 cannotgrow in the absence of histidine unless specific mutations occur. Thepresence of mutagens increases the rates of these mutations. With theaddition of 5 mg of the material per bacterial culture plate, there wasno evidence of cytotoxicity or mutagenicity.

Further evaluation of potential carcinogenicity was performed by invitro testing of chromosomal aberration in mammalian cell culture. Theassay used Chinese hamster ovary cells to detect changes in chromosomalstructure. The chromosomes were observed in metaphase which had beenstained with Giemsa stain. No evidence of chromosomal aberration wasdetected.

Example 4 Hydroxyapatite Bone Filler Synthesis

A preferred composition blended with hydroxyapatite particles withutility as a bone filler may be produced in the following manner: Aratio of one part by weight of PLURONIC® F68NF (poloxamer 188) and twoparts by weight of 22K random AOC (PLURACOL® V-10) are sealed in aheat-resistant glass container and heated to a temperature of 80° C. inan oven. The contents of the flask is stirred for a period of 8 hours at80° C. A ratio of two parts by volume of the liquid polymer is blendedwith three parts of hydroxyapatite particles ranging in size from 50 to300 microns, The composition is maintained at under a vacuum another 16hours at 80° C. to allow air bubbles to escape from within theformulation. The composition is then dispensed directly into 1 ccsyringes and cooled to a temperature of 4° C. After 15 minutes at 4° C.,the syringes are placed into individual foil packets lined with apolyethylene coating. The product is sterilized using an appropriatedose of plasma radiation.

Example 5 Polyethylene Bone Filler Synthesis

A preferred composition blended with high density polyethylene particleswith utility as a bone filler may be produced in the following manner: Aratio of one part by weight of F68NF (poloxamer 188) and two parts byweight of 22K random AOC are sealed in a heat-resistant glass containerand heated to a temperature of 80° C. in an oven. The contents of theflask are stirred for a period of 8 hours at 80° C. The liquid polymeris then blended with an equal mass of high-density polyethyleneparticles ranging in size from 50 to 300 microns. The composition ismaintained under reduced pressure for another 16 hours at 80° C. toallow air bubbles to escape from within the formulation. The compositionis then dispensed directly into 1 cc syringes and cooled to atemperature of 4° C. After 15 minutes at 4° C., the syringes are placedinto individual foil packets lined with a polyethylene coating. Theproduct is sterilized by irradiation.

Example 6 Demineralized Bone Matrix Delivery

Under sterile conditions, demineralized bone matrix (DBM) particles (200to 500 microns in size) were prepared. DBM was blended with thecomposition (2:3) so that each gram of the blend would contain 5 mg ofDBM. A control of DBM blended in a 5% gelatin solution was used.Subclones of mouse myoblast cells were used to determine the bone making(osteogenesis) potential of the blends. This was achieved by assayingthe alkylene phosphatase activity of the cells. The amount of osteogenicactivity, as measured by alkaline phosphatase activity, was the same inboth groups. The results of this study suggest that the composition is asuitable excipient for DBM.

Example 7 Formulation for Drug Delivery

The hydrophobic red dye Sudan IV was chosen as a surrogate forhydrophobic pharmaceutical agents. This dye is widely used as a lipidstain. It was combined with two different block AOC/random AOCcomposition, together with appropriate controls, in order to evaluatethe ability of the composition to disperse the hydrophobic dye into anaqueous environment.

Dye was blended with the composition in two different ways: (1) Melt:the composition was heated to 80° C., 5 mg of dye per gram of wax wasadded and the molten mixture stirred until the dye was fully dissolved.The wax was then allowed to cool to room temperature. (2) Mix: becausesome drugs may be thermally labile, the dye (5 mg/g) and wax werekneaded together at room temperature until they gave a uniformly coloredwax. The waxes evaluated were: (A) a 1:1 blend of poloxamer 188 and 22Krandom AOC; (B) a 1:1 blend of poloxamer 407 and 22K random AOC; (C)pure 22K random AOC. Controls were (D) beeswax and (E) Brij 700 (aPEO-stearate surfactant not suitable for parenteral use). The dye (5mg/g) was added to (C), (D) and (E) by melting, as described above. 0.25g of either A or B was added to 40 ml deionized water and allowed todissolve completely, after which 12.5 mg of dye was added to these twobeakers (A0 and B0) and to a third beaker (F0) containing 40 ml ofdeionised water. Immediately afterwards, 0.25 g of each of A1, A2, B1,B2, C1, D1, and E1 was then added to 40 ml of deionized water in a 50 mlbeaker. All of the beakers were then stirred gently for 2 hours. Takinga stronger red color to indicate a better release of the dye, theresults ranked as follows:

-   E1: Bright red solution with very few dye particles remaining.-   B1: Red solution with a few dye particles remaining.-   A1: Deep pink solution with a few dye particles remaining.-   B2: Dirty red solution with dye particles remaining in suspension.-   A2: Dirty pink solution with dye particles remaining in suspension.-   C1: Pale red solution with dye particles in suspension.-   B0: Very pale green solution with dye particles at the bottom of the    flask.-   A0: Very pale green solution with dye particles loosely aggregating    at the air/water interface.-   F0: Extremely pale green solution, tightly aggregated dye particles    at the air/water interface.-   D1: Clear solution with the floating colored wax showing no change.

The dye was almost completely insoluble in water or solutions of eitherA or B, and was not released from the beeswax, but was dispersed readilyinto solution when fully incorporated into either composition to anextent approaching that of Brij 700, a strong and non-biocompatiblesurfactant. A significant proportion of the dye was also dispersed aftermechanical mixing of the solid dye (coarse powder/crystalline form).These results clearly illustrate the ability of biocompatiblecompositions to effectively release a hydrophobic material from ananhydrous form into an aqueous environment.

Other bioactive agents (e.g., carbohydrates, lipids, natural productsand synthetic analogs thereof, nucleic acids, small moleculessynthesized by man, proteins, antibiotics, antibodies, antigens,chemotherapeutics, imaging and contrast agents, radiotherapeutics,receptors or their ligands) may be used. The depot effects, if any, ofthe composition may also be assayed to determine whether there is anyenhancement of biological activity.

Example 8 Water-Soluble Crayon

A preferred composition was blended with a dye to formulate awater-soluble crayon in the following manner: A ratio of three parts byweight of poloxamer 338 and one part by weight of PLURACOL® V-10 wassealed in a heat-resistant glass container and heated to a temperatureof 80° C. in an oven. Dye was added at a concentration of 5 mg per gramof polymer and stirred until it dissolved. The liquid composition wasthen allowed to remain undisturbed for 16 hours at 80° C. to allow airbubbles to escape from within the liquid. The crayon was formed bypouring the liquid composition into molds and cooling to 4° C. for 15minutes.

Example 9 Biocompatible Cleanser

The usefulness of the composition as a detergent may be assessed. Itssurfactant activity and ability to remove stains or contaminants fromthe surface of a device or instrument can be compared to otherdetergents used in clinical settings. Viscous compositions may be usedin situations where the cleanser is intended to adhere to the surface inneed of deep cleansing; otherwise, non-viscous compositions may be usedfor quick washing and rinsing. The biocompatibility of the compositionswould be advantageous because of the ease with which the cleaned deviceor instrument re-enters use in the clinic. This is an alternative toharsh detergent cleansers.

Example 10 Non-Corrosive Lubricant

The usefulness of the composition as a lubricant may be assessed. Itsability to make a medical device, surgical implant, or instrumentslippery can be compared to other lubricants used in clinical settings.Compositions of varying viscosity (e.g., oil to grease) may be useddepending on the situation. The biocompatibility of composition and itsrapid elimination would be advantageous because of its safety.

Patents, patent applications, books, and other publications cited hereinare incorporated by reference in their entirety.

In stating a numerical range, it should be understood that all valueswithin the range are also described (e.g., one to ten also includesevery integer value between one and ten as well as all intermediateranges such as two to ten, one to five, and three to eight). The term“about” may refer to the statistical uncertainty associated with ameasurement or the variability in a numerical quantity which a personskilled in the art would understand does not affect operation of theinvention or its patentability.

All modifications and substitutions that come within the meaning of theclaims and the range of their legal equivalents are to be embracedwithin their scope. A claim using the transition “comprising” allows theinclusion of other elements to be within the scope of the claim; theinvention is also described by such claims using the transitional phrase“consisting essentially of” (i.e., allowing the inclusion of otherelements to be within the scope of the claim if they do not materiallyaffect operation of the invention) and the transition “consisting”(i.e., allowing only the elements listed in the claim other thanimpurities or inconsequential activities which are ordinarily associatedwith the invention) instead of the “comprising” term. Any of these threetransitions can be used to claim the invention.

It should be understood that an element described in this specificationshould not be construed as a limitation of the claimed invention unlessit is explicitly recited in the claims. Thus, the granted claims are thebasis for determining the scope of legal protection instead of alimitation from the specification which is read into the claims. Incontradistinction, the prior art is explicitly excluded from theinvention to the extent of specific embodiments that would anticipatethe claimed invention or destroy novelty.

Moreover, no particular relationship between or among limitations of aclaim is intended unless such relationship is explicitly recited in theclaim (e.g., the arrangement of components in a product claim or orderof steps in a method claim is not a limitation of the claim unlessexplicitly stated to be so). All possible combinations and permutationsof individual elements disclosed herein are considered to be aspects ofthe invention. Similarly, generalizations of the invention's descriptionare considered to be part of the invention.

From the foregoing, it would be apparent to a person of skill in thisart that the invention can be embodied in other specific forms withoutdeparting from its spirit or essential characteristics. The describedembodiments should be considered only as illustrative, not restrictive,because the scope of the legal protection provided for the inventionwill be indicated by the appended claims rather than by thisspecification.

TABLE 1A COMPOSITION APPEARANCE Polymer Random AOC % Block AOC or AOH %Light Adsorbance Surface Texture Compatibility 22K 98 F68 2 1 very clear1 very smooth Good 22K 95 F68 5 1 very clear 1 very smooth Good 22K 90F68 10 1 very clear 1 very smooth Good 22K 80 F68 20 1 very clear 1 verysmooth Good 22K 70 F68 30 1 very clear 2 smooth Good 22K 60 F68 40 1.5clear to very clear 3 textured Good 22K 50 F68 50 2 clear 3 texturedGood 22K 40 F68 60 3 semi-clear 4 cobblestone Good 22K 30 F68 70 5 whiteopaque 5 coarse Good 22K 20 F68 80 6 white opaque 4 cobblestone Good 22K10 F68 90 6 white opaque 4 cobblestone Good 22K 5 F68 95 7 white opaque4 cobblestone Good 22K 2 F68 98 7 white opaque 4 cobblestone Good 22K 50F88 50 3 semi-clear 1 very smooth Good 22K 70 F98 30 1 very clear 4cobblestone Good 22K 60 F98 40 2 clear 4 cobblestone Good 22K 50 F98 502 clear 4 cobblestone Good 22K 50 F108 50 5 white opaque 4 cobblestoneGood 22K 25 F108 75 5 white opaque 4 smooth to coarse Good 22K 50 F87 502 clear 2 smooth Good 22K 50 F127 50 6 white opaque 4 cobblestone Good22K 50 PEO 1.5K 50 3 semi-clear 2 smooth Good 22K 50 PEO 2.0K 50 2.5semi-clear, clear (edge) 4 cobblestone Good 22K 80 PEO 3.5K 20 2 clear 3textured Good 22K 70 PEO 3.5K 30 2 clear 3 textured Good 22K 60 PEO 3.5K40 2.5 semi-clear, clear 4 cobblestone Good 22K 50 PEO 3.5K 50 4 mottledwhite/clear 5 coarse Good 22K 40 PEO 3.5K 60 4 mottled white/clear 5coarse Good 22K 30 PEO 3.5K 70 4 mottled white/clear 5 coarse Good 22K20 PEO 3.5K 80 5 white 4 cobblestone Good 22K 50 PEO 5.0K 50 2.5semi-clear, clear patches 4 cobblestone Good 22K 50 PEO 7.5K 50 6 whiteopaque 4 cobblestone Partial 22K 50 PEO 12K 50 6 white opaque 4cobblestone Incompatible

TABLE 2A COMPOSITION APPEARANCE Polymer Random AOC % Block AOC or AOH %Light Adsorbance Surface Texture Compatibility 12K 50 F68 50 2 veryclear 4 cobblestone Good 12K 50 F88 50 4 very clear to white (edge) 2smooth Good 12K 40 F98 60 4 mottled white/clear 4 cobblestone Good 12K75 F108 25 1 very clear 3 textured Good 12K 50 F108 50 3 semi-clear 4cobblestone Good 12K 25 F108 75 4 mottled white/clear 4 cobblestone Good12K 50 F127 50 6 white opaque 4 cobblestone Good 12K 50 PEO 2.0K 50 4semi-clear, clear (edge) 4 cobblestone Good 12K 50 PEO 3.5K 50 4 white,semi-clear (edge) 3 textured Good 12K 50 PEO 5.0K 50 4 mottledwhite/clear 4 cobblestone Good 12K 50 PEO 7.5K 50 6 white opaque 4cobblestone Partial 12K 50 PEO 12K 50 6 white opaque 4 cobblestoneIncompatible 12K 50 PEO 20K 50 7 bright white 4 cobblestone Incompatible12K 50 PEO 35K 50 7 bright white 4 cobblestone Incompatible 3.9K  50 F6850 7 bright white 3 textured Incompatible 3.9K  50 F127 50 7 brightwhite 5 coarse Incompatible 3.9K  50 PEO 1.5K 50 7 bright white 3textured Incompatible 3.9K  50 PEO 2.0K 50 7 bright white 3 texturedIncompatible 3.9K  50 PEO 3.5K 50 7 bright white 3 textured Incompatible3.9K  50 PEO 5.0K 50 7 bright white 3 textured Incompatible 3.9K  50 PEO7.5K 50 5 white 0 (liquid paste) Incompatible 3.9K  50 PEO 12K 50 5white 0 (liquid paste) Incompatible

TABLE 1B COMPOSITIONS INITIAL PROPERTIES Random AOC % Block AOC or AOH %Hardness Plasticity Bulk Texture 22K 98 F68 2 1 grease 5 plastic flow 2homogeneous 22K 95 F68 5 2 semi-solid 5 plastic flow 2 homogeneous 22K90 F68 10 3 very soft 4 bends, tears 2 homogeneous 22K 80 F68 20 4 soft4 bends, tears 2 homogeneous 22K 70 F68 30 4 soft 4 bends, tears 2homogeneous; 22K 60 F68 40 5 medium-soft 3 bends, breaks 2 homogeneous22K 50 F68 50 6 medium 3 bends, breaks 2 homogeneous 22K 40 F68 60 6medium 3 bends, breaks 2 homogeneous 22K 30 F68 70 7 medium-hard 2 snaps2 homogeneous 22K 20 F68 80 8 hard 2 snaps 2 homogeneous 22K 10 F68 90 9very hard 1 brittle 2 homogeneous 22K 5 F68 95 9 very hard 1 brittle 2homogeneous 22K 2 F68 98 10 rock hard 1 brittle 2 homogeneous 22K 50 F8850 6 medium 3 bends, breaks 2 homogeneous 22K 70 F98 30 6 medium 3bends, breaks 2 homogeneous 22K 60 F98 40 6 medium 3 bends, breaks 2homogeneous 22K 50 F98 50 7 medium-hard 2 snaps 2 homogeneous 22K 50F108 50 6 medium 3 bends, breaks 2 homogeneous 22K 25 F108 75 9 veryhard 1 brittle 2 homogeneous 22K 50 F87 50 4 soft 4 bends, tears 2homogeneous 22K 50 F127 50 4 soft 4 bends, tears 2 homogeneous 22K 50PEO 1.5K 50 4 soft 4 bends, tears 2 homogeneous 22K 50 PEO 2.0K 50 5medium-soft 3 bends, breaks 2 homogeneous 22K 80 PEO 3.5K 20 3 very soft4 bends, tears 2 homogeneous 22K 70 PEO 3.5K 30 4 soft 4 bends, tears 2homogeneous 22K 60 PEO 3.5K 40 4 soft 4 bends, tears 2 homogeneous 22K50 PEO 3.5K 50 5 medium-soft 3 bends, breaks 2 homogeneous 22K 40 PEO3.5K 60 5 medium-soft 3 bends, breaks 2 homogeneous 22K 30 PEO 3.5K 70 7medium-hard 2 snaps 2 homogeneous 22K 20 PEO 3.5K 80 8 hard 2 snaps 2homogeneous 22K 50 PEO 5.0K 50 7 medium-hard 3 bends, breaks 2homogeneous 22K 50 PEO 7.5K 50 5 medium-soft 4 bends, tears 2homogeneous 22K 50 PEO 12K 50 9 very hard 1 brittle 1 small grains

TABLE 2B COMPOSITION INITIAL PROPERTIES Random AOC % Block AOC or AOH %Hardness Plasticity Bulk Texture 12K 50 F68 50 7 medium-hard 3 bends,breaks 2 homogeneous 12K 50 F88 50 7 medium-hard 3 bends, breaks 2homogeneous 12K 40 F98 60 8 hard 2 snaps 1 small grains 12K 75 F108 25 4soft 4 bends, tears 2 homogeneous 12K 50 F108 50 7 medium-hard 3 bends,breaks 2 homogeneous 12K 25 F108 75 8 hard 2 snaps 1 small grains 12K 50F127 50 4 soft 4 bends, tears 2 homogeneous 12K 50 PEO 2.0K 50 4 soft 4bends, tears 2 homogeneous 12K 50 PEO 3.5K 50 4 soft 4 bends, tears 2homogeneous 12K 50 PEO 5.0K 50 7 medium-hard 3 bends, breaks 2homogeneous 12K 50 PEO 7.5K 50 6 medium 3 bends, breaks 2 homogeneous12K 50 PEO 12K 50 6 medium 3 bends, breaks 1 small grains 12K 50 PEO 20K50 6 medium 3 bends, breaks 1 small grains 12K 50 PEO 35K 50 6 medium 3bends, breaks 0 large grains 3.9K  50 F68 50 7 medium-hard 2 snaps 1small grains 3.9K  50 F127 50 4 soft 1 brittle 1 small grains 3.9K  50PEO 1.5K 50 3 very soft 5 (paste) 1 small grains 3.9K  50 PEO 2.0K 50 8hard 2 snaps 1 small grains 3.9K  50 PEO 3.5K 50 8 hard 2 snaps 1 smallgrains 3.9K  50 PEO 5.0K 50 3 very soft 5 (paste) 1 small grains 3.9K 50 PEO 7.5K 50 3 very soft 5 (paste) 1 small grains 3.9K  50 PEO 12K 503 very soft 5 (paste) 0 large grains

TABLE 1C COMPOSITION PROPERTIES ON WORKING Random AOC % Block AOC or AOH% Hardness Ductility Malleability Cohesion Adhesion 22K 98 F68 2 0.5 522K 95 F68 5 2 5 22K 90 F68 10 2 3 4 −2 6 22K 80 F68 20 3 3 4 −1 5 22K70 F68 30 3 3 3 0 4 22K 60 F68 40 4 3 3 0 2 22K 50 F68 50 5 3 2 0 1 22K40 F68 60 5 2 2 0 0 22K 30 F68 70 5 2 2 0 0 22K 20 F68 80 6 2 1 1 0 22K10 F68 90 7.5 0 0 2 0 22K 5 F68 95 9 0 0 2 0 22K 2 F68 98 9 0 0 2 0 22K50 F88 50 10 2 2 0 0 22K 70 F98 30 5 3 3 0 2 22K 60 F98 40 4 3 2 0 1 22K50 F98 50 5 2 2 0 1 22K 50 F108 50 5 3 2 0 0 22K 25 F108 75 4 3 0 0 022K 50 F87 50 9 3 4 −2 5 22K 50 F127 50 2 3 3 0 2 22K 50 PEO 1.5K 50 3.53 3 0 2 22K 50 PEO 2.0K 50 4 3 3 0 1 22K 80 PEO 3.5K 20 4.5 4 4 −1 5 22K70 PEO 3.5K 30 2.5 4 4 −1 5 22K 60 PEO 3.5K 40 3.5 4 3 0 2 22K 50 PEO3.5K 50 4 4 3 0 1 22K 40 PEO 3.5K 60 5 2 3 0 0 22K 30 PEO 3.5K 70 6 2 20 0

TABLE 2C COMPOSITION PROPERTIES ON WORKING Random AOC % Block AOC or AOH% Hardness Ductility Malleability Cohesion Adhesion 22K 20 PEO 3.5K 80 71 1 1 0 22K 50 PEO 5.0K 50 3 3 3 −1 3 22K 50 PEO 7.5K 50 3 3 4 −2 5 22K50 PEO 12K 50 9 1 0 2 0 12K 50 F68 50 2 3 2 0 2 12K 50 F88 50 2 3 2 0 112K 40 F98 60 0 1 0 2 0 12K 75 F108 25 4 3 4 0 4 12K 50 F108 50 2 3 2 03 12K 25 F108 75 0 1 0 2 0 12K 50 F127 50 4 3 4 0 3 12K 50 PEO 2.0K 50 43 4 −1 6 12K 50 PEO 3.5K 50 4 3 4 −1 6 12K 50 PEO 5.0K 50 4 3 4 0 3 12K50 PEO 7.5K 50 2 3 2 −1 5 12K 50 PEO 12K 50 −3 4 12K 50 PEO 20K 50 −3 412K 50 PEO 35K 50 −3 4 3.9K  50 F68 50 0 −3 3.9K  50 F127 50 0 −3 33.9K  50 PEO 1.5K 50 −3 3.9K  50 PEO 2.0K 50 0 −3 3.9K  50 PEO 3.5K 50 0−3 3.9K  50 PEO 5.0K 50 −3 3.9K  50 PEO 7.5K 50 −3 3.9K  50 PEO 12K 50−3 Hardness: 1 = grease, 2 = semi-solid, 3 = very soft, 4 = soft, 5 =medium soft, 6 = medium, 7 = medium-hard, 8 = hard, 9 = very hard, 10 =rock hard Ductibility: 0 = crumbles, 1 and 2 = fractures, 3 = does notfracture, 4 = stretchable Malleability: 0 = not deformable, 1 = poorlymoldable, 2 = moldable with work, 3 = readily moldable, 4 = verymoldable Adhesion: 0 = non-tacky, 1 = slight tack, 2 = tacky, 3 = verytacky, 4 = moderately sticky, 5 = sticky, 6 = very sticky Cohesion: −2 =cohesion, −1 = soft/reduced cohesion, 0 = cohesive, 1 = hard/barelycohesive, 2 = crumbles

1. A composition consisting of: (i) solid or porous particles; (ii) arandom copolymer having a molecular mass of at least 5 kg/mol, andcomprising ethylene oxide and one or more other alkylene oxide(s); and(iii) a non-random polymer comprising one or more alkylene oxide(s). 2.The composition of claim 1, wherein said composition can adhere to bodytissue.
 3. The composition of claim 1, wherein said composition isbiocompatible and substantially non-toxic.
 4. The composition of claim1, wherein the random copolymer and the non-random polymer aresubstantially non-metabolizable and readily eliminated in unmodifiedform.
 5. The composition of claim 1, wherein said composition issubstantially anhydrous.
 6. The composition of claim 1, wherein saidcomposition has a consistency at 25° C. of a viscous oil to a hard wax.7. The composition of claim 1, wherein said random copolymer has amolecular mass of at least 10 kg/mol.
 8. The composition of claim 1,wherein said random copolymer has a molecular mass of at least 20kg/mol.
 9. The composition of claim 1, wherein said random copolymer hasa molecular mass of not more than 25 kg/mol.
 10. The composition ofclaim 1, wherein said random copolymer has a molecular mass of not morethan 50 kg/mol.
 11. The composition of claim 1, wherein said randomcopolymer has a molecular mass of not more than 200 kg/mol.
 12. Thecomposition of claim 1, wherein said random copolymer has a molecularmass from 1 kg/mol to 1000 kg/mol.
 13. The composition of claim 1,wherein said other alkylene oxide(s) is propylene oxide and/or butyleneoxide.
 14. The composition of claim 1, wherein said other alkylene oxideis propylene oxide, and said random copolymer has (i) a molecular massfrom 15 kg/mol to 30kg/mol and (ii) a mass ratio of the ethylene oxideto the propylene oxide from 25:75 to 75:25.
 15. The composition of claim14, wherein said random copolymer has a molecular mass from 20 kg/mol to25 kg/mol.
 16. The composition of claim 14, wherein said randomcopolymer has a mass ratio of the ethylene oxide to the propylene oxidefrom 40:60 to 60:40.
 17. The composition of claim 1, wherein saidnon-random polymer of alkylene oxide(s) is a homopolymer.
 18. Thecomposition of claim 17, wherein said homopolymer has a molecular massfrom 1 kg/mol to 20 kg/mol.
 19. The composition of claim 17, whereinsaid homopolymer has a molecular mass from 1 kg/mol to 10 kg/mol. 20.The composition of claim 17, wherein said homopolymer is poly(ethyleneoxide).
 21. The composition of claim 1, wherein said non-random polymeris selected from the group consisting of poloxamer, meroxapol,poloxamine, and reverse poloxamine.
 22. The composition of claim 1,wherein said non-random polymer is a block copolymer.
 23. Thecomposition of claim 22, wherein said block copolymer is a poloxamerselected from the group consisting of poloxamer 108, poloxamer 188,poloxamer 238, poloxamer 288, poloxamer 338, poloxamer 235, poloxamer237, poloxamer 335, and poloxamer
 407. 24. The composition of claim 22,wherein said block copolymer is a copolymer of ethylene oxide andpropylene oxide.
 25. The composition of claim 24, wherein said blockcopolymer has a molecular mass from 10 kg/mol to 50 kg/mol.
 26. Thecomposition of claim 24, wherein said block copolymer has a mass ratioof the ethylene oxide to the propylene oxide from 25:75 to 95:5.
 27. Thecomposition of claim 22, wherein said block copolymer is a triblockcopolymer of ethylene oxide and propylene oxide.
 28. The composition ofclaim 27, wherein said triblock copolymer has a molecular mass from 4kg/mol to 20 kg/mol.
 29. The composition of claim 28, wherein saidtriblock copolymer has a mass ratio of the ethylene oxide to thepropylene oxide from 25:75 to 95:5.
 30. The composition of claim 24,wherein said block copolymer has (i) a molecular mass from 6 kg/mol to10 kg/mol and (ii) a mass ratio of the ethylene oxide to the propyleneoxide from 60:40 to 90:10.
 31. The composition of claim 24, wherein saidblock copolymer has (i) a molecular mass from 10 kg/mol to 15 kg/mol and(ii) a mass ratio of the ethylene oxide to the propylene oxide from60:40 to 90:10.
 32. The composition of claim 1, wherein said particlesare from 10% by volume to 64% by volume.
 33. The composition of claim 1,wherein said particles have a size from 35 microns to 500 microns. 34.The composition of claim 1, wherein said particles are selected from thegroup consisting of bone chips or powder, demineralized bone,hydroxyapatite, polyethylene, and any combination thereof.
 35. A methodof using the composition of claim 1, which comprises administering saidcomposition to a subject.
 36. A process of making a product useful formedicine or surgery, which comprises suspending (a) solid or porousparticles in (b) a carrier consisting of (i) at least one randomcopolymer having a molecular mass of at least 5 kg/mol, and comprisingethylene oxide and one or more other alkylene oxide(s) and (ii) at leastone non-random polymer comprising one or more alkylene oxide(s).